Single- and Repeat-Dose Pharmacokinetics of Sublingual Sufentanil NanoTab in Healthy Volunteers

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1 Single- and Repeat-Dose Pharmacokinetics of Sublingual Sufentanil NanoTab in Healthy Volunteers Pamela P. Palmer, MD, PhD AcelRx Pharmaceuticals, Inc. October 20,

2 Sufentanil: A Superior Opioid Approved for intravenous (IV) and epidural administration 1 High therapeutic index 2 No active metabolites 3 Opioid Therapeutic index 2 Methadone 12 Meperidine 28 Morphine 70 Rapid transmucosal uptake Hydromorphone 232 Fentanyl 300 Sufentanil 25,000 Therapeutic index = median lethal dose (LD 50 )/ lowest median effective dose (ED 50 ) 2 1. Sufenta (sufentanil citrate) [package insert]. Decatur, IL: Taylor Pharmaceuticals; De Castro J. Practical applications and limitations of analgesic anesthesia: a review. Acta Anaesthesiol Belg. 1976;27: Monk JP, Beresford R, Ward A. Sufentanil. A review of its pharmacological properties and therapeutic use. Drugs. 1988;36:

3 NanoTab: Efficient Transmucosal Delivery NanoTab: a novel oral transmucosal dosage form Key attributes: Bioadhesive Low saliva response Minimal swallowed drug Enhanced transmucosal uptake Consistent pharmacokinetics High bioavailability Lower maximum concentration (C max ) than IV infusion Cartridge with 40 NanoTabs NanoTab 3

4 AcelRx Development Programs Indication Preclinical Phase 1 Phase 2 Phase 3 Approved Inpatient acute postoperative pain ARX-01: Sufentanil NanoTab patient-controlled t t analgesia (PCA) System Cancer breakthrough pain ARX-02: Sufentanil NanoTab breakthrough pain (BTP) Management System Procedural sedation anxiolysis and analgesia ARX-03: Sufentanil/Triazolam i l NanoTab 4

5 Noninvasive Handheld Sublingual PCA System IV PCA Pump Sufentanil NanoTab PCA System 5 Key potential benefits No programming errors No IV-related complications Improved patient t mobility High patient and caregiver satisfaction

6 Objective and Methods Objective: To evaluate overall Phase 1 pharmacokinetic data from both singleand multiple-dose sublingual administrations of Sufentanil NanoTab (10 mcg) Methods: Two Phase 1 studies (ARX-F01-01 and ARX-C-002) evaluated healthy young subjects aged 18 to 45 years 33 subjects (17 male, 16 female) from both studies combined receivedasingle10mcgnanotab 12 of these subjects in a separate arm of the study also received a 10 mcg NanoTab every 20 minutes for a total of 4 doses All subjects received IV sufentanil 5 mcg as a comparator 6

7 NanoTab Oral Transmucosal Delivery: Consistent and Therapeutically Useful Plasma Profile Sufentanil plasma concentration: single sublingual NanoTab 10 mcg versus IV infusion i 5 mcg (over 10 minutes) Pla asma sufenta anil concentra ation (pg/m ml) ± SD T max = 41 ± 13 min (%CV = 32) Time (min) 7 IV, intravenous; SD, standard deviation; T max, time to maximum concentration.

8 Repeat Dosing at 20 Minute Intervals: Titrating to an Effective Concentration Sufentanil plasma concentration with repeat dosing ntration Plasma sufe entanil conce (pg g/ml) ± SE 15 mcg (simulation) 10 mcg (actual) Therapeutic range 1 5 mcg (simulation) Mean T max = 84.6 ± 4.3 min (%CV = 18) Doses Time (min) 8 SE, standard error; T max, time to maximum concentration; CV, coefficient of variation. 1. Lehmann KA, et al. Postoperative patient-controlled analgesia with sufentanil: analgesic efficacy and minimum effective concentrations. Acta Anaesthesiol Scand. 1991;35:

9 Sufentanil NanoTab Pharmacokinetics PK parameters NanoTab single dose 10 mcg (n = 33*) NanoTab repeat dosing 10 mcg every 20 min x 4 (n = 12) Bioavailability 78% 88% C max 21.4 pg/ml 78.7 pg/ml (%CV) (36%) (26%) T max (%CV) Half-life (%CV) 43.8 min (34%) 2.1 h (38%) 84.6 min [24.6 min after last dose] (18%) 3.5 h (29%) *Results of the two Phase 1 studies are combined for 10 mcg single dose analysis. 9 PK, pharmacokinetic; C max, maximum concentration; CV, coefficient of variation; T max, time to maximum concentration.

10 Sufentanil NanoTab PCA System: Development Update Completed three Phase 2 studies, including major orthopedic and major abdominal surgeries (158 patients received active drug) The Sufentanil NanoTab 15 mcg dose was the most efficacious, with no difference in adverse events versus 5 or 10 mcg strengths Median usage was 10 NanoTabs over 12 hours Very low adverse event profile for sedation and oxygen desaturation Sufentanil NanoTab PCA System 10

11 11 Thank You